{"doi":"10.1016/j.molmet.2025.102182","title":"microRNA-1 regulates metabolic flexibility by programming adult skeletal muscle pyruvate metabolism","abstract":"OBJECTIVE: Metabolic flexibility refers to the ability of tissues to adjust cellular fuel choice in response to conditional changes in metabolic demand and activity. A loss of metabolic flexibility is a defining feature of various diseases and cellular dysfunction. This study investigated the role of microRNA-1 (miR-1), the most abundant microRNA in skeletal muscle, in maintaining whole-body metabolic flexibility. METHODS: We used an inducible, skeletal muscle-specific knockout (KO) mouse model to examine miR-1 function. Argonaute 2 enhanced crosslinking and immunoprecipitation sequencing (AGO2 eCLIP-seq) and RNA-seq analyses identified miR-1 target genes. Metabolism was investigated using metabolomics, proteomics, and comprehensive bioenergetic and activity phenotyping. Corroborating information was provided from cell culture, C. elegans, and exercised human muscle tissue. RESULTS: miR-1 KO mice demonstrated loss of diurnal oscillations in whole-body respiratory exchange ratio and higher fasting blood glucose. For the first time, we identified bona fide miR-1 target genes in adult skeletal muscle that regulated pyruvate metabolism through mechanisms including the alternative splicing of pyruvate kinase (Pkm). The maintenance of metabolic flexibility by miR-1 was necessary for sustained endurance activity in mice and in C. elegans. Loss of metabolic flexibility in the miR-1 KO mouse was rescued by pharmacological inhibition of the miR-1 target, monocarboxylate transporter 4 (MCT4), which redirects glycolytic carbon flux toward oxidation. The physiological down-regulation of miR-1 in response to hypertrophic stimuli caused a similar metabolic reprogramming necessary for muscle cell growth. CONCLUSIONS: These data identify a novel post-transcriptional mechanism of whole-body metabolism regulation mediated by a tissue-specific miRNA.","journal":"Molecular Metabolism","year":2025,"id":519687,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.964,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":306113,"name":"Bailey D. Peck","orcid":null,"position":1,"is_corresponding":false},{"id":920413,"name":"McLane M. Montgomery","orcid":"0000-0002-8253-6858","position":2,"is_corresponding":false},{"id":1063817,"name":"Benjamin I. Burke","orcid":"0000-0003-0228-1750","position":3,"is_corresponding":false},{"id":669925,"name":"Jensen Goh","orcid":null,"position":4,"is_corresponding":false},{"id":1388637,"name":"Abigail B Franco","orcid":"0000-0002-4913-3686","position":5,"is_corresponding":false},{"id":1036796,"name":"Xia Qin","orcid":"0000-0001-9689-1730","position":6,"is_corresponding":false},{"id":1036798,"name":"Katarzyna Goljanek‐Whysall","orcid":"0000-0001-8166-8800","position":7,"is_corresponding":false},{"id":406572,"name":"Brian McDonagh","orcid":"0000-0003-2534-4427","position":8,"is_corresponding":false},{"id":393090,"name":"Jared M. McLendon","orcid":"0000-0002-1002-5872","position":9,"is_corresponding":false},{"id":1216308,"name":"Pieter J Koopmans","orcid":null,"position":10,"is_corresponding":false},{"id":1388638,"name":"Daniel Jacko","orcid":"0000-0002-9330-4702","position":11,"is_corresponding":false},{"id":1229137,"name":"Kirill Schaaf","orcid":null,"position":12,"is_corresponding":false},{"id":270722,"name":"Wilhelm Bloch","orcid":"0000-0003-1786-8853","position":13,"is_corresponding":false},{"id":1228689,"name":"Sebastian Gehlert","orcid":"0000-0001-6940-3084","position":14,"is_corresponding":false},{"id":282073,"name":"Kevin A. Murach","orcid":"0000-0003-2783-7137","position":15,"is_corresponding":false},{"id":333399,"name":"Kelsey H. Fisher‐Wellman","orcid":"0000-0002-0300-829X","position":16,"is_corresponding":false},{"id":499325,"name":"Ryan L. Boudreau","orcid":"0000-0002-9800-5349","position":17,"is_corresponding":false},{"id":142302,"name":"Yuan Wen","orcid":null,"position":18,"is_corresponding":false},{"id":282076,"name":"John J. McCarthy","orcid":"0000-0003-4522-5601","position":19,"is_corresponding":false},{"id":669282,"name":"Ahmed Ismaeel","orcid":"0000-0003-4025-3945","position":0,"is_corresponding":true}],"reference_count":79,"raw_metadata":null,"created_at":"2026-07-19T02:49:23.618703Z","pmid":"40490136","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}